Novel Therapy for Glucose Intolerance in HIV Disease

HIV 疾病中葡萄糖不耐受的新疗法

• 批准号: 7046684
• 负责人: MARIE C GELATO
• 金额: $ 35.22万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046684
• 关键词: HIV infections; alternative medicine; antiAIDS agent; biopsy; chelation therapy; chromium; clinical research; clinical trials; combination chemotherapy; diabetes mellitus therapy; diet therapy; dietary supplements; drug adverse effect; enzyme activity; glucose metabolism; glucose tolerance; human subject; human therapy evaluation; insulin receptor; insulin sensitivity /resistance; medical complication; nutrition related tag; patient oriented research; phosphatidylinositol 3 kinase; phosphorylation; prediabetic state

DESCRIPTION (provided by applicant): Multi-drug regimens in HIV disease are associated with an incidence of insulin resistance of at least 50%. Insulin resistance is associated with the development of dyslipidemia, type 2 diabetes, and hypertension. This constellation of metabolic abnormalities is known to cause accelerated atherosclerosis in patients with type 2 diabetes. The current guidelines from the American Diabetes Association and the American College of Endocrinologists recommends screening for glucose intolerance and treatment for patients at high risk of diabetes. This proposal seeks to establish a treatment option for insulin resistance / glucose intolerance in HIV/AIDS prior to the transition to overt diabetes. Chromium picolinate is a dietary supplement that has been shown to improve insulin sensitivity in patients with type 2 diabetes mellitus and, in a preliminary study, in HIV+ patients. This dietary supplement has a wide margin of safety and may provide substantial therapeutic benefit without serious side-effects. This proposal will test the hypothesis that chromium picolinate improves insulin-stimulated glucose uptake by increasing the insulin receptor-mediated tyrosine phosphorylation of insulin receptor substrate-1, resulting in increased activity of phosphatidylinositol 3-kinase. The hypothesis will be addressed in two specific aims. Specific Aim 1 will assess quantitative improvements in insulin-mediated glucose disposal in a double-blind, placebo-controlled study of chromium supplementation with 1000 microgram (19.2 mu/mol) of chromium as chromium picolinate, over a two month course of therapy of subjects with glucose intolerance (defined with an oral glucose tolerance test, OGTT). Both safety and efficacy (improved glucose disposal with a hyperinsulineminc, euglycemic clamp and insulin secretion, OGTT) will be evaluated. The cellular mechanism for improved insulin sensitivity with chromium supplementation will be determined in Specific Aim 2 by assessing the effect of chromium supplementation on the insulin-stimulated activity of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase in biopsies of adipose tissue. Thus, this research will document the therapeutic benefit of chromium supplementation for insulin resistance / glucose intolerance in HIV disease and will provide a mechanistic framework to explain how chromium supplementation enhances insulin action.

描述（由申请人提供）：HIV疾病中的多药治疗方案与至少50％的胰岛素抵抗发生率有关。 胰岛素抵抗与血脂异常，2型糖尿病和高血压的发展有关。 已知该代谢异常的星座在2型糖尿病患者的患者中会导致动脉粥样硬化加速。美国糖尿病协会和美国内分泌学院的当前指南建议对高糖尿病风险的患者进行葡萄糖不耐症和治疗。该提案旨在在过渡到明显的糖尿病之前，建立胰岛素抵抗 /葡萄糖不耐症的治疗选择。 Picolinate Chromium picolinate是一种饮食补充剂，已证明可以改善2型糖尿病患者的胰岛素敏感性，并且在一项初步研究中，在HIV+患者的初步研究中。这种饮食补充剂具有很大的安全性，可以在没有严重副作用的情况下提供可观的治疗益处。该提案将检验以下假设：Picolinate铬通过增加胰岛素受体介导的胰岛素受体底物1的酪氨酸磷酸化来改善胰岛素刺激的葡萄糖摄取，从而导致磷脂酰糖苷3-激酶的活性增加。该假设将以两个具体目标解决。具体目标1将评估胰岛素介导的葡萄糖处置的定量改进，在一项双盲，安慰剂对照的研究中，用1000微克（19.2 MU/mol）作为铬铬铬作为铬的铬，在两个月的治疗中，用葡萄糖不耐受（定义）对受试者进行了两个月的治疗（定义）（定义）。将评估安全性和功效（用高胰岛素素，尤基糖夹和胰岛素分泌的葡萄糖处置改善，OGTT）。通过评估补充铬补充对胰岛素受体底物-1相关磷脂酰肌醇3-激酶在脂肪组织的活检中的胰岛素刺激活性的影响，将在特定的目标2中确定胰岛素敏感性改善胰岛素敏感性的细胞机制。因此，这项研究将记录补充铬在HIV疾病中胰岛素抵抗 /葡萄糖不耐症的治疗益处，并将提供一个机械框架来解释补充铬的补充剂。